Molecular insights into the interaction of Coptis teeta protoberberine alkaloids with human topoisomerase 1B-DNA...

Human topoisomerase 1B (hTopo1B) is a validated anticancer target due to its key role in relieving torsional stress during DNA replication and transcription, as well as its overexpression in rapidly proliferating tumor cells. Camptothecin (CPT) and its derivatives are principal hTopo1B-targeting agents but face challenges including lactone ring instability, dose-limiting toxicities, and acquired drug resistance. This research investigated seven protoberberine alkaloids from Coptis teeta alkaloids-berberine, coptisine, epiberberine, berberastine, jatrorrhizine, palmatine, and fetidine as potential CPT-like hTopo1B inhibitors using comprehensive computational methods. Density functional theory (DFT) calculations showed that six of the seven alkaloids had HOMO-LUMO gaps (2.608-3.015 eV) and electrophilicity indices similar to CPT, suggesting a capacity for charge transfer and DNA intercalation. Molecular docking of the hTopo1B-DNA binary complex (PDB:1A36) revealed that all compounds stabilized the covalent cleavage complex through π-π stacking and hydrogen bonds at the scissile site, with coptisine and epiberberine showing the strongest binding affinities (----10.32 and -10.53 kcal/mol, respectively). Molecular dynamics simulations over 250 ns confirmed the structural stability of the complexes, with low RMSD and RMSF values and minimal fluctuations in the radius of gyration. MM/GBSA and MM/PBSA binding free energy analyses consistently ranked epiberberine as the strongest binder (DG = -18.86 and -14.12 kcal/mol), followed by berberine and coptisine. Per-residue decomposition identified key contacts with the DNA bases DT118, DA17, and DA14, as well as with the protein residues GLU179 and GLY201. All protoberberine analogs showed drug-likeness in ADME profiling, good oral availability, and no PAINS alerts. These findings suggest that protoberberine alkaloids from C.teeta, especially epiberberine, coptisine, and berberine, are promising candidates for next-generation hTopo1B-targeted anticancer therapeutics. Experimental validation is required to confirm the proposed mechanism.